The National Institute on Drug Abuse's 2009 Strategic Plan highlights prevention of drug use initiation among youth using novel interventions as a key objective. Early initiation of substance use is a serious public health problem, with national surveys suggesting close to one third of eighth graders have used some form of illicit drug. Prevention with youth from disadvantaged communities is particularly urgent. Early and continued exposure to adversity-widespread in such communities--is associated with increased risks for early drug use initiation and subsequent substance use disorders. The proposed R34 project is a randomized controlled study to assess the impact of a 24-week, school-based mindfulness and yoga intervention to prevent substance use among disadvantaged, urban youth. The intervention is informed by findings in cognitive neuroscience, which suggest that mindfulness practices enhance cognitive and emotion regulation capacities. Evidence suggests that strengthening those capacities may improve key social-emotional precursors of substance use initiation, such as internalizing and externalizing symptoms, thereby reducing risks for substance use problems. Participants will be 266 fifth and sixth graders recruited from six K-8 Baltimore City schools. Schools will be randomized either to an intervention or control condition. Social, emotional, behavioral, and academic functioning and substance use norms, attitudes, and use will be assessed at baseline, post-intervention, and 6- and 12-month follow ups. Data will be collected via youth self-reports, neurocognitive tests, teacher reports, and academic records. We will assess intervention outcomes, as well as hypothesized moderators (e.g., stress exposure) and mediators (e.g., self- regulatory capacities) of intervention effects. Feasibility of this research is enhanced by longstanding collaboration among the Johns Hopkins Bloomberg School of Public Health, Pennsylvania State University's Prevention Research Center, and the Baltimore-based Holistic Life Foundation, which specializes in teaching mindfulness and yoga to urban youth. A pilot randomized trial by our team provided encouraging evidence for intervention feasibility and preliminary outcomes. The proposed study will build on that work and will provide effect size estimates and other data to inform the design of a larger-scale randomized controlled R01 trial of program efficacy. If successful, the intervention will not only reduce substance use initiation but will also promote positive youth development across emotional and behavioral domains. The intervention has potential for dissemination locally and nationally.